P物质/神经激肽1受体系统在肿瘤治疗中的研究进展

doi:10.16098/j.issn.0529-1356.2019.06.030

摘要/Abstract

摘要：

P物质（SP）是第1个被发现的速激肽家族成员，广泛分布于哺乳动物的中枢神经系统和外周神经系统，参与多种生理和病理过程。神经激肽受体（NKRs）包括NK1R、NK2R和NK3R，它们是G-蛋白耦联受体家族成员。SP是NK1R内源性的高亲和性和高选择性配体。越来越多的实验结果表明，SP/NK1R系统参与了肿瘤的发生过程。因此，NK1R有可能成为肿瘤治疗的新靶点。我们就SP/NK1R系统在肿瘤中的表达水平，以及SP/NK1R系统作为新靶点在肿瘤治疗领域的研究进展做一简要综述。

关键词: P物质/神经激肽1受体系统, 分布, 肿瘤治疗

Abstract:

Substance P (SP) is the first identified peptide in tachykinin family, which widespreadly distributes in both central and peripheral nervous systems of mammals and is involved in many physiological and pathological processes. Neurokinin receptors (NKRs) belong to the G-protein coupled receptor family, including NK1R, NK2R and NK3R. SP has the highest affinity and is the selectivity ligand for NK1R. Cumulative experimental results have shown that SP/NK1R system is involved in the cancer process and NK1R has the potential to be a new target for cancer treatment. In this review, we focus on the expression levels of SP/NK1R system in cancers and how to develop SP/NK1R system as a new target for cancer treatment.

Key words: Substance P/neurokinin 1 receptor system, Distribution, Cancer treatment

陈麒黄荷淼葛晨涛付彩云. P物质/神经激肽1受体系统在肿瘤治疗中的研究进展[J]. 解剖学报, 2019, 50(6): 861-864.

CHEN Qi HUANG He-miao GE Chen-tao FU Cai-yun. Advance of substance P/neurokinin receptor 1 system in cancer treatment[J]. Acta Anatomica Sinica, 2019, 50(6): 861-864.

参考文献

［1］ Devane CL. Substance P: a new era, a new role［J］. Pharmacotherapy, 2001, 21(9):1061-1069.

［2］ Goldsmith LE, Kwatra MM. NK1 (substance P) receptor［J］.UCSD Molecule Pages, 2012, 1(1):1-8.

［3］ Wang H, Zhang YQ, Ding YQ, et al. Immumohistochemical localization of neurokinin B receptor (NK3) in the central nervous system of the mouse［J］. Acta Anatomica Sinica, 2002, 33(1):21-27. (in Chinese)

王红, 张远强, 丁玉强,等. 神经激肽B受体在小鼠中枢神经系统内的定位分布［J］. 解剖学报, 2002, 33(1):21-27.

［4］ Bright FM, Byard RW, Vink R, et al. Normative distribution of substance P and its tachykinin neurokinin-1 receptor in the medullary serotonergic network of the human infant during postnatal development［J］. Brain Res Bull, 2018, 137:319-328.

［5］ Warner SC, Walsh DA, Laslett LL, et al. Pain in knee osteoarthritis is associated with variation in the neurokinin 1/substance P receptor (TACR1) gene［J］. Eur J Pain, 2017, 21(7):1277-1284.

［6］ Li YX, Liang WM, Hu Y, et al. Effect of heroin withdrawal and relapse on the expressions of 5-hydroxy tryptamine and substance P in colon of rats［J］. Acta Anatomica Sinica, 2011, 42(4):527-531. (in Chinese)

李一欣, 梁文妹, 胡赟,等. 海洛因戒断与复吸对大鼠结肠5-羟色胺和P物质表达的影响［J］. 解剖学报, 2011, 42(4):527-531.

［7］ Liang WM, Li YX, Huang Zh, et al. Effects of heroin dependence on the expression of substance P and neuropeptide Y in the ventral tegmental area and nucleus accumbens of the rat brain［J］. Acta Anatomica Sinica, 2012, 43(2):150-154. (in Chinese)

梁文妹, 李一欣, 黄智,等. 海洛因依赖对大鼠中脑腹侧被盖区、伏隔核神经元P物质和神经肽Y表达的影响［J］. 解剖学报, 2012, 43(2):150-154.

［8］ Wang W, Wu ShX, Wang YY. c-fos antisense oligodeoxynucleotide reduces bee venom-induced PPTA mRNA expression in the neurons of spinal dorsal horn［J］. Acta Anatomica Sinica, 2000, 31(Suppl):57-60. (in Chinese)

王文, 武胜昔, 王亚云. c-fos反义寡核苷酸减弱蜜蜂毒诱导的前速激肽原AmRNA在脊髓后角神经元的表达［J］. 解剖学报, 2000, 31(Suppl):57-60.

［9］ Suvas S. Role of substance P neuropeptide in inflammation, wound healing, and tissue homeostasis［J］. J Immunol, 2017, 199(5):1543-1552.

［10］ Baek SM, Yu SY, Son Y, et al. Substance P promotes the recovery of oxidative stress-damaged retinal pigmented epithelial cells by modulating Akt/GSK-3beta signaling［J］. Mol Vis, 2016, 22:1015-1023.

［11］ Yang L, Sui W, Li Y, et al. Substance P inhibits hyperosmotic stress-induced apoptosis in corneal epithelial cells through the mechanism of akt activation and reactive oxygen species scavenging via the neurokinin-1 receptor［J］. PLoS One, 2016, 11(2):e0149865.

［12］ Zhang Z, Zheng W, Xie H, et al. Up-regulated expression of substance P in CD8(+) T cells and NK1R on monocytes of atopic dermatitis［J］. J Transl Med, 2017, 15(1):93-110.

［13］ Fu S, Mei G, Wang Z, et al. Neuropeptide substance P improves osteoblastic and angiogenic differentiation capacity of bone marrow stem cells in vitro［J］. Biomed Res Int, 2014, 2014:596023.

［14］ Mashaghi A, Marmalidou A, Tehrani M, et al. Neuropeptide substance P and the immune response［J］. Cell Mol Life Sci, 2016, 73(22):4249-4264.

［15］ Mu?oz M, Cove?as R. Involvement of substance P and the NK-1 receptor in cancer progression［J］. Peptides, 2013, 48:1-9.

［16］ Carter MS, Krause JE. Structure, expression, and some regulatory mechanisms of the rat preprotachykinin gene encoding substance P, neurokinin A, neuropeptide K, and neuropeptide gamma［J］. J Neurosci, 1990, 10(7):2203-2214.

［17］ Culman J, Unger T. Central tachykinins: mediators of defence reaction and stress reactions［J］. Can J Physiol Pharm, 1995, 73(7):885-891.

［18］ Guo CJ, Lai JP, Luo HM, et al. Substance P up-regulates macrophage inflammatory protein-1β expression in human T lymphocytes［J］. J Neuroimmunol, 2002, 131(1-2):160-167.

［19］ Dib M, Zsengeller Z, Mitsialis A, et al. A paradoxical protective role for the proinflammatory peptide substance P receptor (NK1R) in acute hyperoxic lung injury［J］. Am J Physiol Lung Cell Mol Physiol, 2009, 297(4):L687-L697.

［20］ Singh D, Joshi DD, Hameed M, et al. Increased expression of preprotachykinin-Ⅰand neurokinin receptors in human breast cancer cells: implications for bone marrow metastasis［J］. Proc Natl Acad Sciusa, 2000, 97(1):388-393.

［21］ Muo?z M, González-Ortega A, Rosso M, et al. The substance P/neurokinin-1 receptor system in lung cancer: focus on the antitumor action of neurokinin-1 receptor antagonists［J］. Peptides, 2012, 38(2):318-325.

［22］ Khare VK, Albino AP, Reed JA. The neuropeptide/mast cell secretagogue substance P is expressed in cutaneous melanocytic lesions［J］. J Cutan Pathol, 1998, 25(1):2-10.

［23］ Palma C, Bigioni M, Irrissuto C, et al. Anti-tumour activity of tachykinin NK 1 receptor antagonists on human glioma U373 MG xenograft［J］. Brit J Cancer, 2000, 82(2):480-486.

［24］ Munoz M, Rosso M, Covenas R, et al. Neurokinin-1 receptors located in human retinoblastoma cell lines: antitumor action of its antagonist, L-732,138［J］. Invest Ophth Vis Sci, 2007, 48(6):2775-2781.

［25］ Gonzalez Moles MA, Mosqueda-Taylor A, Esteban F, et al. Cell proliferation associated with actions of the substance P/NK-1 receptor complex in keratocystic odontogenic tumours［J］. Oral Oncol, 2008, 44(12):1127-1133.

［26］ Brener S, Gonzlez-Moles MA, Tostes D, et al. A role for the substance P/NK-1 receptor complex in cell proliferation in oral squamous cell carcinoma［J］. Anticancer Res, 2009, 29(6):2323-2329.

［27］ Gonzalez-Santana A, MarreroHernandez S, Dorta Ⅰ, et al. Altered expression of the tachykinins substance P/neurokinin A/hemokinin-1 and their preferred neurokinin 1/neurokinin 2 receptors in uterine leiomyomata［J］. Fertil Steril, 2016, 106(6):1521-1529.

［28］ Esteban F, Gonzalez-Moles MA, Castro D, et al. Expression of substance P and neurokinin-1-receptor in laryngeal cancer: linking chronic inflammation to cancer promotion and progression［J］. Histopathology, 2009, 54(2):258-260.

［29］ Chen XY, Ru G Q, Ma YY, et al. High expression of substance P and its receptor neurokinin-1 receptor in colorectal cancer is associated with tumor progression and prognosis［J］. Onco Targets Ther, 2016, 9:3595-3602.

［30］ Friess H, Zhu Z, Liard Ⅴ, et al. Neurokinin-1 receptor expression and its potential effects on tumor growth in human pancreatic cancer［J］. Lab Invest, 2003, 83(5):731-743.

［31］ Mu?oz M, Rosso M, Robles-Frias MJ, et al. The NK-1 receptor is expressed in human melanoma and is involved in the antitumor action of the NK-1 receptor antagonist aprepitant on melanoma cell lines［J］. Lab Invest, 2010, 90(8):1259-1269.

［32］ Munoz M, Rosso M, Carranza A, et al. Increased nuclear localization of substance P in human gastric tumor cells［J］. Acta Histochem, 2017, 119(3):337-342.

［33］ Garnier A, Ilmer M, Becker K, et al. Truncated neurokinin-1 receptor is an ubiquitous antitumor target in hepatoblastoma, and its expression is independent of tumor biology and stage［J］. Oncol Lett, 2016, 11(1):870-878.

［34］ Ge C, Huang H, Huang F, et al. Neurokinin-1 receptor is an effective target for treating leukemia by inducing oxidative stress through mitochondrial calcium overload［J］. PNAS, 2019, 116(39): 19635-19645.

［35］ Grady EF, Garland AM, Gamp PD, et al. Delineation of the endocytic pathway of substance P and its seven-transmembrane domain NK1 receptor［J］. Mol Biol Cell, 1995, 6(5):509-524.

［36］ Feng F, Yang J, Tong L, et al. Substance P immunoreactive nerve fibres are related to gastric cancer differentiation status and could promote proliferation and migration of gastric cancer cells［J］. Cell Biol Int, 2011, 35(6):623-629.

［37］ Medrano S, Gruenstein E, Dimlich RV. Substance P receptors on human astrocytoma cells are linked to glycogen breakdown［J］. Neurosci Lett, 1994, 167(1-2):14-18.

［38］ Meshki J, Douglas SD, Lai JP, et al. Neurokinin 1 receptor mediates membrane blebbing in HEK293 cells through a Rho/Rho-associated coiled-coil kinase-dependent mechanism［J］. J Biol Chem, 2009, 284(14):9280-9289.

［39］ Ma J, Yuan S, Cheng J, et al. Substance P Promotes the Progression of Endometrial Adenocarcinoma［J］. Int J Gynecol Cancer, 2016, 26(5):845-850.

［40］ Li J, Zeng Q, Zhang Y, et al. Neurokinin-1 receptor mediated breast cancer cell migration by increased expression of MMP-2 and MMP-14［J］. Eur J Cell Biol, 2016, 95(10):368-377.

［41］ Huang C, Li Y, Guo Y, et al. MMP1/PAR1/SP/NK1R paracrine loop modulates early perineural invasion of pancreatic cancer cells［J］. Theranostics, 2018, 8(11):3074-3086.

［42］ Munoz M, Covenas R. Neurokinin-1 receptor antagonists as antitumor drugs in gastrointestinal cancer: a new approach［J］. Saudi J Gastroenterol, 2016, 22(4):260-268.

［43］ Berger M, Neth O, Ilmer M, et al. Hepatoblastoma cells express truncated neurokinin-1 receptor and can be growth inhibited by aprepitant in vitro and in vivo［J］. J Hepatol, 2014, 60(5):985-994.

［44］ St?nder S. Pruritus. NK-1 Antagonists［M］. Cham: Springer International Publishing, 2016: 407-414.

［45］ Ikeda M, Shida M, Hirasawa T, et al. Efficacy of the oral neurokinin-1 receptor antagonist aprepitant for nausea and vomiting induced by cisplatin and carboplatin in Japanese patients with gynecological cancer［J］. J Obstet Gynaecol Res, 2017, 43(10):1613-1620.

［46］ Hesketh PJ, Schnadig ID, Schwartzberg LS, et al. Efficacy of the neurokinin-1 receptor antagonist rolapitant in preventing nausea and vomiting in patients receiving carboplatin-based chemotherapy［J］. Cancer, 2016, 122(15):2418-2425.

［47］ Niu XL, Hou JF, Li JX. The NK1 receptor antagonist NKP608 inhibits proliferation of human colorectal cancer cells via Wnt signaling pathway［J］. Biol Res, 2018, 51(1):14-22.

［48］ Mu?oz M, Martinez-Armesto J, Coveas R. NK-1 receptor antagonists as antitumor drugs: a survey of the literature from 2000 to 2011［J］. Expert Opin Ther Pat, 2012, 22(7):735-746.

［49］ Akazawa T, Kwatra SG, Goldsmith LE, et al. A constitutively active form of neurokinin 1 receptor and neurokinin 1 receptor‐mediated apoptosis in glioblastomas［J］. J Neurochem, 2009, 109(4):1079-1086.

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